Breast cancer is a disease characterized by the malignancy of cells in the mammary tissue and the random growth of the malignant cells. It is said that this cancer develops in a morbidity of 1 in 25-30 women in Japan or 1 in 8-10 women in Europe and the United States. It is also known that men suffer from breast cancer although the morbidity is low. From recent studies, it has been found that patients with breast cancer are composed of a variety of populations with different biological characteristics, and responses to treatment and prognosis significantly vary among patients of different populations. Specifically, it is suggested that breast cancer can be roughly classified into five molecular subtypes through the comprehensive gene expression analysis on DNA chips. In routine clinical practice, however, breast cancer is often classified into four subtypes by detecting the expression of estrogen receptor, progesterone receptor, and Her2 protein, so that the treatment plan can be determined based thereon. In principle, the treatment to breast cancer is performed by means of surgical therapy, and chemotherapy and radiation therapy are further employed in combination depending on cancer staging, metastasis, general conditions, and classified breast cancer subtypes. When providing chemotherapy, it is particularly important to evaluate a drug(s) to be administered to a target patient and to select an appropriate treatment plan, depending on the breast cancer subtype as described above (Non-Patent Document 1).
Among these subtypes, Her2-positive breast cancer, which accounts for approximately 25% of all breast cancer cases, shows a high degree of malignancy, a high rate of metastasis, and a poor prognosis. Accordingly, improvement in the outcome of treatment of Her2-positive breast cancer remains crucial in the future.
Trastuzumab (tradename: Herceptin®, Chugai Pharmaceutical, Co., Ltd.) is an antibody drug approved by the Ministry of Health, Labor, and Welfare in Japan, which exerts an anti-tumor effect by binding to Her2 protein on the surface of Her2-positive breast cancer cells. Trastuzumab is the first-line agent that was used for treatment of Her2-positive breast cancer. However, some patients with Her2-positive breast cancer show no response to Trastuzumab (which means that Trastuzumab is not effective), and some patients develop serious side effects, such as cardiac failure, respiratory difficulty, or allergies as a result of Trastuzumab administration. In current clinical diagnosis, whether or not the breast cancer is Her2-positive is determined by detecting the overexpression of Her2 protein and/or the amplification of a gene for Her2 protein on the genome by immunohistochemical means. With these techniques, however, patients who have Her2-positive breast cancer but show no response to Trastuzumab or patients who may develop side effects cannot be identified.
Specifically, it is known that the percentage of patients showing response to Trastuzumab was 35% or lower among patients that had the overexpression of Her2 protein detected by immunohistochemical means and were treated with a single agent, i.e. Trastuzumab alone (Non-Patent Document 2). In methods for examining whether breast cancer is Her2-positive by detecting the overexpression of Her2 protein by immunohistochemical means or by detecting the amplification of a gene for Her2 protein on the genome (which is an examination method as disclosed in Non-Patent Document 3), the percentage of patients showing response to Trastuzumab is known to be 65.2% or lower among patients who were subjected to treatment with Trastuzumab in combination with another anti-tumor agent (Non-Patent Document 3). More specifically, the accuracy for prediction of Trastuzumab response as determined by the examination method of Non-Patent Document 3, which is currently employed in clinical sites, is at most 65.2%.
Drug therapy for treatment of breast cancer has achieved remarkable progression in recent years, and it is becoming possible to select a variety of therapeutic agents depending on cancer properties. In such situation, if the response to Trastuzumab therapy in breast cancer patients could be predicted with higher accuracy than is possible with the method that is currently employed to identify the Her2-positive breast cancer, the method for treatment of a patient with Her2-positive breast cancer could be selected more easily and, as a result, chemotherapy effects could be maximized while side effects could be minimized.
Reports on the response to Trastuzumab therapy in patients with Her2-positive breast cancer that have been made in the past are: activation of PTEN protein (Non-Patent Document 4); gene amplification and/or overexpression of cyclin E (Non-Patent Document 5); and control of Her2 protein expression with miR-125a and/or miR-125b (Non-Patent Document 6).
Non-Patent Document 4 discloses that PTEN expression levels in a patient with Her2-positive breast cancer is evaluated by an immunohistochemical technique, that cells in which PTEN expression is suppressed are less susceptible to Trastuzumab-mediated growth inhibition, and that the PTEN expression level is correlated with inhibition of disease progression in a patient with Her2-positive breast cancer by Trastuzumab.
Non-Patent Document 5 discloses the evaluation of cyclin E protein expression levels in patients with Her2-positive breast cancer responsive to Trastuzumab therapy by immunohistochemical means, and that the percentage of patients who have not experienced disease progression was higher in the groups of patients showing higher cyclin E protein expression levels among patients who have been subjected to treatment with Trastuzumab and other anticancer agents.
Non-Patent Document 6 discloses that elevated miR-125a and miR-125b expression levels lead to lowered expression levels of Her2 protein, which is targeted by Trastuzumab.
It is also known that the expression levels of let-7a (Patent Document 1), let-7b (Patent Document 1), and miR-145 (Patent Document 2) are lowered in breast cancer patients, and the expression level of miR-200c (Patent Document 3) is elevated in breast cancer patients.